>> So first up is Namandje Bumpus,
associate dean for basic research
and our newly named director of the pharmacology department
here in the school of medicine.
Namandje will talk about the basic biology
that makes certain medicines less effective
in African-Americans.
>> Thank you.
Okay, so thanks everybody for coming and hanging out
and listening to my talk.
So we, in my lab, we're really interested in understanding
how different people, and different populations
of people as well, respond to medicines.
So, one thing that we're interested in is looking
at genetics of drug response
and genetics with drug processing.
And we've been particularly interested in looking at how
African Americans and other members of the African diaspora
are differentially responding to certain medicine
and kind of understanding the reasons
for that from a biological perspective.
So we primarily focus in on a process
called drug metabolism.
And the reason we do this, because this is actually
the process that really controls the response
we get in many ways to a majority of drugs.
So basically for oral medications, most medicines we use
are orally administered and oral medications tend to be
lipophilic or fat soluble so that our bodies
can absorb them.
And then we need a way to get rid of them.
Our body basically looks at them as a foreign molecule,
we don't want these drugs to hang around forever,
so we have this process called drug metabolism
that changes this fat soluble drug
into something more water-soluble
that can be excreted from our body,
so primarily excreted in urine.
So this process, metabolism, happens in the intestine,
it happens all over the body, but the intestine
and the liver, the liver is really a site where we have
an abundance of the proteins that carry out drug metabolism,
it's a protein driven process.
And so since drugs have to pass through the system,
they're absorbed by our intestine,
they go through the portal vein to our liver,
oral administered drugs must pass through our liver
where metabolism occurs.
That means that metabolism's really controlling
how much of the drug we swallowed
ends up in our bloodstream.
So when the proteins act on the drug,
they formed other products we call drug metabolites
and those can circulate in our blood
and go into our urine as well.
But essentially this process really controls how much drug
makes it to your bloodstream after you swallow a medication.
There are many, many, many drug metabolizing proteins,
the one that we'll talk about that's really responsible
for most drug metabolism are called the cytochromes P450
or P450 or CYP for short.
So I focused a little more in on how this works
just at a high level here.
So P450s are important because it turns out
that about 80% of drugs on the market are cleared by P450.
So their metabolized by P450s and that's the major pathway
by which our body clears these drugs.
So what happens is if we swallow drug it goes through,
like we looked at a slide before, through in our stomach.
It goes into our GI tract and moves to the portal vein,
into the liver, then we have individual liver cells,
just blowing out to show what happens there.
The individual liver cell, so here our hepatocyte liver cell
contains these drug metabolizing proteins.
So here just showing a P450, there are also other kinds
of drug metabolizing proteins too.
But this drug, when it's metabolized by a P450 gets changed
and what P450s mostly do is insert an oxygen into the drug.
When they insert that oxygen that's enough to make
that drug much more water-soluble and it can be excreted.
So drugs, through blood flow, they come in through transport
often, or other mechanisms, can undergo metabolism
by P450s, we get what we call a metabolite,
this drug now with this oxygen inserted,
and then it can go back into our blood.
And so what I'm showing here is we have a drug
kind of at the end of this blood vessel
that also has several metabolites and the important thing
to think about there is that many drugs are metabolized
actually such that 99% of it or more is metabolized.
So this drug that you swallow, it may turn out
that after it goes through your liver, only 1% or less
of what you swallow is actually what ends up in your blood.
So P450s really control the drug response for many drugs
and it's important then to think about how they're acting
on these drugs and understand that since much
of what we end up taking actually turns out
to be metabolites.
So what does this look like in a drug?
So just to kind of show you this.
So here I'm showing you an HIV drug, Nevirapine,
and I only wanted you to see in real life what this looks
like on a structure.
So I told you P50s insert an oxygen.
So here we have an oxygen inserted on the drug,
so metabolite, we see a different metabolite here,
an oxygen inserted, that third metabolite oxygen inserted.
They all have different names, 3-hydroxy, 2-hydroxy,
12-hydroxy, 'cause it's just where
an oxygen's been inserted.
But the big point here is that one drug,
whether it's Nevirapine or caffeine, for instance,
that many of us are exposed to, can be metabolized
to many different metabolites.
It doesn't have to be one, it can be many,
many different metabolites.
Also, I told you P405s we can call them CYP,
and that's what we call individual P450s, CYP.
So here's one P450 called CYP2B6.
They're just named basically based upon how they look,
their structure and the order in which we found them.
But all this to say that we can have one drug
that's metabolized to many metabolites
and also can be metabolized by more than one P450.
So these metabolites can go on and be excreted in urine,
I mentioned they're more water-soluble
they also can have toxicity.
So the major drug induced toxicity is liver toxicity
and that's 90% of the time because a toxic metabolite
was formed most often by a P450.
So for instance, with Tylenol toxicity,
it happens because P450s metabolized Tylenol
for something that's toxic.
So it's really important to understand this process
for many different kind of standpoints.
So with that in mind, we're really interested
in genetic variation in P450s because you can imagine
if they really control how much of a drug ends up
in your bloodstream circulating and therefore how much drug
is able to do its thing pharmacologically
and do what we need it to do therapeutically, if there are
genetic differences between people and P450 activity
that could mean that we could all respond differently
to drugs because they are being metabolized differently.
So it turns out that P450s are highly genetically variant,
genetic variation has been found in most P450s.
These variants can change the efficacy of a drug or how well
it can work therapeutically.
It can also change whether or not you're likely to get
a drug induced toxicity.
As I mentioned, many metabolites are responsible
for drug induced toxicities
because they're toxic themselves.
So if there's variation between you and me in the formation
of that toxic metabolites, one of us may be more likely
to have an adverse reaction to the drug than someone else.
So we're interested in genetics
from kind of both of those perspectives.
Interestingly this variation seems to be really related
to ethnicity and geographic region of ancestry.
So we've been interested in looking at that
and specifically trying to understand genetic variation
in African populations versus European populations
and within the context of United States, but also globally.
So I'm gonna tell you one short story with a compound,
a drug, that we've done this work with.
So this is just a model, it's not the only drug
that could be sensitive to differences
between people and metabolism.
But I just wanted to give you an example where we've seen
this play out.
So this drug is Maraviroc, it's an FDA-approved drug
for HIV treatment.
It is also a candidate for HIV prevention,
so preventing someone from becoming infected,
they could take this drug to prevent infection.
And that's because Maraviroc is an HIV entry inhibitor.
So in host cells, so in, you know, a human cell,
there is a receptor or a protein that HIV binds to.
And so Maraviroc blocks that interaction,
it blocks the ability of HIV to be able to bind
to the human protein, to the human receptor
that it utilizes to get inside of human cells.
So it's an entry inhibitor.
So we wanted to determine, there are differences observed
in people between, in outcomes with this drug.
It's often as a result used
as kind of salvage therapy for people.
Used in people that have failed other regimens
and kind of, you know, they need something else
to move on to.
So because of some of the variability in outcomes
we became interested in understanding,
was there a genetic mechanism at play?
So to first do that we wanted to figure out
which P450s metabolized Maraviroc.
So this is just a summary.
So our only take home here is that, in humans we have
57 P450, there are, you know, a small subset shown here
that are really involved in drug metabolism, the other ones
do lots of other things in the body.
We, in the lab, at the bench, in test tubes
with purified proteins tested
whether each of these P450s could metabolize more Maraviroc.
We did that because we wanted to then be able to in humans
look for potential genetic differences in one
of these P450s that could impact outcomes.
We were really interested to find that the majority
of Maraviroc metabolism was carried out
by a P450 called 3A5.
This was interesting to us because this 3A5,
this other P450 that has the next biggest slice of the pie,
3A4, are very similar.
They're over 90% similar.
So it's actually very rare to see drugs
that are primarily metabolized by one more than the other.
But because they're so similar people often don't even look
to see if there are any differences there.
Another reason why it's important to think about 3A5
primarily metabolizing Maraviroc and why it was so striking
to us is because it's a very, very,
very highly polymorphic enzyme.
So it turns out that what we consider the wild type,
or the most active, people that really have functional
active 3A5 activity, so they can functionally metabolize
things that 3A5 metabolizes, that that's mostly actually
associated with people of African descent.
So many African populations.
Like if you look at Bantus in Uganda and other folks
about 95 to 99% of those individuals have 3A5
and it functions well.
Over 60% of African Americans have 3A5
and it functions well.
You see the opposite when you look at people
of European ancestry.
So over 90% of people of European descent,
including European-Americans, had instead a mutated version
of 3A5 that leads to low or no expression.
This is interesting to us because there's a real lack
of diversity in clinical studies.
So most drug development clinical trials are done
in European-American males in their 20s in the US.
So that means that if a drug is metabolized by this 3A5
and 90% of those people in that trial don't even have it
we could be looking at safety and choosing a dose
based on people that don't even really metabolize this drug.
You could see a totally different story then when you try
the drug in African-Americans.
So we think it's important to really start looking for this,
but also we want as proof of concept to see whether we could
see any differences in Maraviroc metabolism.
So we designed a small study.
We used 24 healthy volunteers, or 24 people that were HIV
negative that weren't taking this drug.
They look it just to volunteer for our study.
We had people in various groups: people that had 3A5,
so those were basically African American people,
people that had both 3A5 and these variants where they don't
have it, so that was kind of a mix, there were some
African American in that group, a couple
of European Americans, and then people that had only
the variants that lead to no expression,
and that ended up being a group of European Americans.
We gave them a single dose of Maraviroc at the dose
that you would get therapeutically and we collected blood
at various concentrations of the 32 hours and we measured
the concentrations of Maraviroc in their blood.
And what we were really interested to see
was that it looks like genetics really does affect
our exposure to Maraviroc.
So this is just showing us, basically,
if we look at the amounts of Maraviroc we could detect
at each of those concentrations
and use that as a matter of exposure.
So if we plot a graph where on the X axis we have time,
the time we collected blood to look at drug,
and on the Y axis we have the amount
of Maraviroc we could find we can look at the area
under that curve we get as a way to think about
our overall exposure to the drug.
And so what we saw was that people that did not have 3A5,
so this would be European-Americans, mostly people
of European descent that didn't have 3A5, had a certain
level of exposure that we see here.
And that exposure was actually significantly greater
than people that did have functional 3A5.
So people like me, I'm someone that I have functional 3A5,
I'm wild type for it, so I would be in this group
that says two underneath it, where we have much lower
Maraviroc because we're metabolizing it more quickly.
When we modeled this we actually found that people like me
and many African Americans that metabolize Maraviroc
more quickly would probably need double the dose
of other people, people that don't have 3A5,
so many European-Americans.
We'd need double the dose
to get the same therapeutic outcome.
So that means that we're susceptible to treatment failure,
viral resistance, all types of things.
So this does not split completely down the line
of ethnicity or ancestry,
but it's highly correlated with that and I think really
suggests the need to think about genetics
in the drug development process.
So I just wanted to summarize
kind of my key takeaway points.
So one is that drug metabolism is really critical.
We think of metabolism, also, we think more about, you know,
weight loss and things like that, but actually metabolism
of drugs is a critical pathway for clearance a majority
of drugs and that genetic variation of drug metabolism
really controls drug outcomes and this can be different
between people and different between different populations.
African Americans in general are under studied,
people of African descent in general are under studied from
a biological perspective.
But genetics, African American genetics,
is severely understudied.
And in addition, we really need to start thinking
about diversifying clinical trials.
So if we continue to do clinical trials in people
of European descent primarily we are going to be missing
toxicities, we're gonna be missing drug outcome variation
that could be very important.
And I think this is particularly timely
when we're talking about drug development for something like
COVID-19 that disproportionately is impacting
African Americans.
If we don't diversify our trials we aren't gonna actually
know how the drug is gonna work in us.
So it's just something I think for us to all think about.
And that's all I have.
And thanks for listening.
>> Host: Great, thank you very much.
Couple of questions, so John Davies asks,
"Is there anything related to diet that might help explain
why some medications also may not affect African-Americans
in the same ways?"
>> Diet can certainly have an impact.
We don't fully understand but we know that a lot
of P450s, their expression can be cranked up
by lots of things.
So for instance, alcohol can really increase expression,
which is why you're not supposed to take Tylenol
and drink alcohol.
You crank up Tylenol metabolism when you drink alcohol
with it and you make more of the toxic metabolites.
So certainly diet can have an impact, and environment, yes.
>> Host: Sam Miller asks, "Are there significant differences
in pain, medication metabolism between racial groups?
Are there ways to take these differences into account
when making plans for pain management?"
>> This is something that's not been studied enough
so we don't know.
There are anecdotal observations that people make
for pain meds and for many other classes of drugs,
but it's just really understudied.
So I think we need to design trials to really look at that.
But I think that more than we recognize,
they're probably drugs that we need to be altering
and thinking about the impact on various populations.
And genetics specifically, not just race only,
but individual genetics, I think have to be considered.
>> Host: Okay, so Annie Green asks,
"What can medical institutions do to regain the trust
of members of the African American community
who may be justifiably hesitant to participate
in medical research due to unethical practices
by researchers in the past?"
>> Yeah, so I think that's something that we think about
a lot when I'm doing my studies.
I think one thing that helps is diversifying our workforce.
Seeing more African American scientists,
more African American physicians,
I think helps to build that trust.
Having more African American people involved in the process.
I think that with health inequity and health disparities
that if we don't address that diversity in trials
but also the lack of diversity in scientists and positions
that we can't really combat health inequities.
That part of it is really making sure that we are part
of every step in the decision making process
and that we are represented.
And I think that by us being involved more
there will be more trust built.
>> Host: Great, alright. Well, thank you very much again.